EP1049673A1 - Amidines heterocycliques utilisees comme inhibiteurs de la kallicreine - Google Patents

Amidines heterocycliques utilisees comme inhibiteurs de la kallicreine

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Publication number
EP1049673A1
EP1049673A1 EP99903676A EP99903676A EP1049673A1 EP 1049673 A1 EP1049673 A1 EP 1049673A1 EP 99903676 A EP99903676 A EP 99903676A EP 99903676 A EP99903676 A EP 99903676A EP 1049673 A1 EP1049673 A1 EP 1049673A1
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European Patent Office
Prior art keywords
alkyl
hooc
carry
radicals
pyridyl
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EP99903676A
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German (de)
English (en)
Inventor
Dorit Baucke
Udo Lange
Helmut Mack
Werner Seitz
Hans Wolfgang HÖFFKEN
Wilfried Hornberger
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp

Definitions

  • the present invention relates to new five-membered heterocyclic amidines, their preparation and their use as competitive inhibitors of kininogenases such as kallikrein and trypsin-like serine proteases, especially thrombin.
  • the invention also relates to pharmaceutical compositions which contain the compounds as active constituents, and to the use of the compounds as anti-inflammatory agents, thrombin inhibitors and anticoagulants.
  • Kininogenases are serine proteases that release vasoactive peptides from kininogens, the so-called kinins (bradykinin, kallidin and Met-Lys-bradykinin). Kininogens are multifunctional proteins that occur in cascade coagulation and inflammation reactions. As inhibitors, they protect cells from destruction by cysteine proteases (Müller Esterl, 1985, FEBS Lett. 182, 310-314). Important kininogenases are plasma kallikrein, tissue kallikrein and mast cell tryptase.
  • kinins such as bradykinin and kallidin are vasoactive peptides that affect a variety of biological processes. They play an essential role in inflammatory processes. By increasing vascular permeability, they lead to hypotension and edema. Furthermore, they are very potent pain-producing substances in the body and are of great importance as cellular mediators in the pathophysiology of asthma, allergic rhinitis and arthritis (KD Bhoola, CD. Figueroa, K. Worthy, Pharmacological Reviews 1992, 44 (1), 1- 80).
  • PKSI-527 the hydrochloride of N- (trans-4-aminomethylcyclohexylcarbonyl) -L-phenylalanine-4-carboxymethyl-anilide, is also an effective inhibitor for this kininogenase (Wanaka, Ohamoto et al., Thromb. Res. 1990 , 57 (6), 889-895).
  • Thrombin belongs to the group of serine proteases and plays a central role as a terminal enzyme in the blood coagulation cascade. Both the intrinsic and the extrinsic coagulation cascade lead to several reinforcement levels
  • thrombin Formation of thrombin from prothrombin.
  • the thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and platelet aggregation, which in turn increases the formation of thrombin by binding platelet factor 3 and coagulation factor XIII and a whole series of highly active mediators.
  • thromboin formation and action are central events in the development of both white, arterial and red, venous thrombi and therefore potentially effective targets for pharmaceuticals.
  • thrombin inhibitors are able, independently of cofactors, to completely inhibit the effects of free thrombin as well as that bound to platelets. They can prevent thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis in the acute phase and serve as anticoagulants in the extracorporeal circulation (cardiopulmonary machine, hemodialysis). They can also be used in general for thrombosis prophylaxis, for example after surgery.
  • PTCA percutaneous transluminal coronary angioplasty
  • lysis in the acute phase and serve as anticoagulants in the extracorporeal circulation (cardiopulmonary machine, hemodialysis). They can also be used in general for thrombosis prophylaxis, for example after surgery.
  • Thrombin inhibitor is described (C. Mattson et al., Folia Haematol, 109, 43 to 51, 1983).
  • thrombin-inhibitory activity of peptidic ketones, fluorinated alkyl ketones, and of keto esters, boric acid derivatives, phosphoric acid esters and ⁇ -ketocarboxamides can also be explained with this serine interaction (EP 118280, 195212, 362002, 364344, 410411, 471651, 589741, 293881 506420 530167; WO 92/07869, 94/08941).
  • EP 0 601 459 and WO 95/23609 represent a further development, the agmatine being replaced by an arylamidine residue.
  • EP 0 672 658 also describes a thrombin inhibitor with an amidinothiophene (Example 65).
  • the invention relates to the use of the compounds of the formula I.
  • A, B, D, E and F have the following meaning and their use as kallikrein or thrombin inhibitors:
  • R 1 HOOC-, C ⁇ - 6 -alkyl-OOC-, aryl-C 0 - 4 -alkyl-OOC or -OH,
  • R 2 is H, C 4 alkyl or R 1 - (CH 2 ) m -,
  • R 3 H or C ⁇ -. 4 -alkyl-
  • R 9 is H or C 3 alkyl
  • R 10 is H or C 4 alkyl
  • R 11 is H or C 4 alkyl
  • amino acid derivatives represented by B are preferably (D) -configured, azetidinecarboxylic acid or proline in D are preferably (L) -configured.
  • R 6 -W, -CH 2 - (CR 7 R 8 ) -W with W C ⁇ _ 8 alkyl-, 2-thienyl, 3-thienyl,
  • 3-indolyl-, 4-imidazolyl-, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-, phenyl-, which up to three identical or different radicals of the group CH 3 -, CF 3 -, CH 3 O- , HO-, BnO-, F- or Cl- can carry, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, which cycloalkyl radicals can carry up to four methyl radicals, adamantyl, indanyl, or -CH-W with W Ci-s-alkyl, 2-thienyl, 3-thienyl, 3-indolyl, 4-imidazol-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, phenyl, which up to can carry three identical or different radicals of the group C ⁇ _ 4 -alkyl-, CF 3
  • R 7 is H, C 8 alkyl, phenyl, which can carry up to three identical or different radicals from the group C 4 alkyl, CF 3 , C 4 alkoxy, F or Cl, C 3 _ 8 cycloalkyl, which can carry up to four identical or different C 4 alkyl radicals,
  • R 8 is H or C 4 alkyl
  • R 8 is H or C 4 alkyl
  • HOOC- (CH 2 ) t - (t 1, 2 or 3), (HOOC-CH 2 ) 2 -CH-, HOOC-CH 2 -CH (COOH) -, HOOC-CH (C ⁇ - 4 - Alkyl) -, HOOC-C (Ci- 4 -alkyl) 2 -, C ⁇ _ 6 -alkyl-OOC- (CH 2 ) t -,
  • amino acid derivatives represented by B are preferably (D) -configured, azetidinecarboxylic acid or proline in D are preferably (L) -configured.
  • R 6 -W or -CH 2 - (CR 7 R 8 ) -W with W C ⁇ - 8 alkyl-, 2-thienyl,
  • 3-thienyl, 3-indolyl, 4-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, phenyl, which contains up to three identical or different radicals from the group CH 3 -, CF 3 -, CH 3 can carry 0-, HO-, BnO-, F- or Cl-, cyclopentyl, cyclohexyl, cycloheptyl-, which can carry up to four methyl radicals, or - (CR 7 R 8 ) -W with W C ⁇ _ 8 alkyl, 2-thienyl, 3-thienyl, 3-indolyl, 4-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, phenyl, which is up to three identical or different Radicals of the group CH 3 -, CF 3 -, CH 3 0-, HO-, BnO-, F- or Cl- can carry, cyclopenty
  • amino acid derivatives represented by B are preferably (D) -configured, azetidinecarboxylic acid or proline in D are preferably (L) -configured.
  • Adagly Adamantylglycine AIBN: Azobisisobutyronitrile
  • Aze Azetidine carboxylic acid
  • Chg cyclohexylglycine
  • Me methyl ⁇ -MeCha: ⁇ -methylcyclohexylalanine ß, ß-Me 2 Cha: 2-amino-3-cyclohexyl-3-methyl-butyric acid or ß, ß-dimethylcyclohexylalanine
  • RT room temperature
  • s singlet sb: singlet broad t: triplet t: tertiary tBu: tertiary butyl tert: tertiary
  • TBAB tetrabutylammonium bromide
  • TEA trietylamine
  • TFAA trifluoroacetic anhydride thiaz: thiazole thioph: thiophene Z: benzyloxycarbonyl 18th
  • cycloalkyl by itself or as part of another substituent contains saturated or cyclic hydrocarbon groups which contain the stated number of carbon atoms.
  • C 3 _ 8 -cycloalkyl refers to saturated alicyclic rings with 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl-cyclohexyl, cycloheptyl or cyclooctyl,
  • alkyl by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case.
  • C ⁇ - 4 alkyl for example methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl;
  • C; L _ 6 alkyl for example C 4 alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3,3-dimethyl -butyl;
  • C 8 alkyl for example C 6 alkyl, heptyl or octyl.
  • alkoxy by itself or as part of another substituent means a linear or branched alkyl chain radical which has the length indicated in each case and is bonded to the parent compound in question via an oxygen atom.
  • C ⁇ _ 4 -alkoxy means, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy, 2-methyl-2-propoxy, 2-methyl-l-propoxy, 1-butoxy, 2-butoxy.
  • the invention further relates to compounds that form the structural element
  • Contain NH 2 in which D and E have the meaning given above and on the nitrogen atom of building block D there is a hydrogen atom, a protective group, an optionally substituted natural or unnatural amino acid, an optionally substituted carboxylic acid or an optionally substituted alkyl radical.
  • the structural fragment is valuable as a component of serine protease inhibitors and in particular thrombin and kallikrein inhibitors. 19
  • the invention further relates to the intermediates of the formulas Ha and Ilb
  • the new intermediates are used to prepare compounds I and are valuable building blocks for the synthesis of serine protease inhibitors.
  • the compounds of the formula I can be present as such or in the form of their salts with physiologically tolerated acids.
  • acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, succinic acid, hydroxy acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
  • IR 1 is C 6 alkylOOC, aryl Co 4 alkylOOC and / or F is hydroxyamidine
  • those compounds which are converted in vivo into pharmacologically active compounds of the general formula I are regarded as prodrugs of the compounds of the general formula I.
  • In vivo metabolism can e.g. take place in the liver during the "first pass" metabolism.
  • the compounds of formula I are competitive inhibitors of trypsin-like serine proteases, especially thrombin and kininogenases such as kallikrein. They can be used for the following indications: 20th
  • epithelial cells e.g. vascular endothelial cells
  • DIC disseminated intravascular coagulation
  • thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC, plasminogen activators from the salivary glands of animals and the recombinant and mutant forms of all these substances,
  • the new compounds for the therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep venous thrombosis, pulmonary embolism, myocardial or cerebral infarction and unstable angina can continue to be used for the therapy of disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators to shorten the reperfusion time and extend the reocclusion time.
  • Further preferred fields of application are the prevention of thrombin-dependent early reocclusion and late restenosis after percutaneous transluminal coronary angioplasia, the prevention of thrombin-induced proliferation of smooth muscle cells, the prevention of active thrombin accumulation in the CNS (eg in M. Alzheimer's disease), the fight against tumors and the prevention of mechanisms that lead to adhesion and metastasis of tumor cells.
  • the new compounds can also be used to coat artificial surfaces such as hemodialysis membranes and the hose systems and lines required for them, as well as oxygenators for extravascular circulation, stents and heart valves.
  • the new compounds can also be used in diseases whose pathomechanism is based directly or indirectly on the proteolytic action of kininogenases, in particular kallikrein, e.g. for inflammatory diseases such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal inflammatory diseases.
  • diseases whose pathomechanism is based directly or indirectly on the proteolytic action of kininogenases, in particular kallikrein, e.g. for inflammatory diseases such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal inflammatory diseases.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active ingredient per person is between about 10 and 2000 mg with oral administration and between about 1 and 200 mg with parenteral administration. This dose can be given in 2 to 4 single doses or once a day as a depot form.
  • the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, dragées, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be combined with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, 22
  • Emulsifiers, solvents, retardants, antioxidants and / or propellants are processed (see H. Sucker et al.: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).
  • the application forms thus obtained normally contain the active ingredient in an amount of 0.1 to 99% by weight.
  • the building blocks A, B, D and E are preferably constructed separately beforehand and used in a suitably protected form (see scheme I-III).
  • the nitrile function is converted into the amidine group either via the classic Pinner synthesis (R. Boder, DG Neilson, Chem. Rev. 1962, 6_1, 179) or via a modified Pinner synthesis which proceeds as an intermediate via iminothioester salts (H. Vieweg et al., Pharmazie 1984, 3.9, 226) or directly according to the method of A. Eschenmoser Helv. Chimica Acta £ 9 (1986) 1224. Subsequently protecting groups still present in the molecule are preferably cleaved off by acid hydrolysis.
  • building block E is not installed as HE-CN, but as HE-CONH 2 in the synthesis, one of the protected ones is used
  • building block E can be used as HE-CSNH 2 in the synthesis.
  • Scheme II describes the linear structure of the molecule I by alkylation, reductive amination or Michael addition of HBP to suitable, optionally protected A building blocks to (P) -ABP, cleavage of the C-terminal protective group to (P) -AB-OH, Coupling with HDP to (P) -ABDP, cleavage of the C-terminal protective group to (P) -ABD-OH, coupling with HE-CN to (P) -ABDE-CN and conversion of this intermediate to the end product analogous to Scheme I.
  • HE-CONH 2 , HE-CSNH 2 / HEC (NH) NH 2 , HEC (NP) NH 2 , HEC (NP) NHP can also be used, in which case the coupled intermediate (P ) -ABDE-CONH 2 dehydrated to (P) -ABDE-CN or converted to (P) -ABDE-CSNH 2 using Lawesson's reagent.
  • Scheme III describes a very efficient way of preparing the compounds I by a convergent synthesis.
  • the appropriately protected building blocks (P) -AB-OH and HDE-CN are coupled together and the resulting intermediate (P) -ABDE-CN is converted into the end product in accordance with Scheme I. 25th
  • HD- ⁇ -CONH 2 or HDE-CSNH 2 can also be used, in which case the coupled intermediate (P) -ABDE-CONH 2 is dehydrated to (P) -ABDE-CN or in (P) -ABDE-CSNH 2 is transferred.
  • Boc, Cbz or Fmoc are used as N-terminal protective groups; C-terminal protective groups are methyl, tert-butyl and benzyl. If there are several protective groups in the molecule, they must be orthogonal to one another if they are not to be split off simultaneously.
  • Boc protective groups are removed by means of dioxane / HCl or TFA / DCM, Cbz protective groups by hydrogenolysis or using HF.
  • the saponification of ester functions takes place with LiOH or NaOH in an alcoholic solvent or in dioxane / water.
  • t-Butyl esters are cleaved with TFA or HC1.
  • Reversed phase HPLC separations were carried out with acetonitrile / water and HOAc buffer.
  • the starting compounds can be prepared using the following methods:
  • building blocks A for the alkylation e.g. -Bromacetic acid- tert-butyl ester, ß-bromopropionic acid-tert. -butyl ester, ⁇ -bromo-propionic acid tert. -butyl ester, ⁇ -bromobutyric acid tert-butyl ester, -bromobutyric acid tert. -butyl ester, THP-protected bromoethanol, THP-protected ⁇ -bromopropanol, for reductive amination e.g. Dihydroxyacetone, acetone dicarboxylic acid di-tert. butyl ester and for Michael addition e.g.
  • Cyclopentylglycine was prepared by hydrolysis with 6N hydrochloric acid from N-acetyl- (D, L) -cyclopentylglycine, which 25 according to the literature specification of J.T. Hill and F.W. Thin,
  • Boc-1-tetralinylglycine was prepared starting from 1,2-dihydronaphthalene. 1,2-Dihydronaphthalene was first converted into 1-tetralyl bromide with HBr (analogous to J. Med. Chem 1994, 37, 1586). The bromide was then reacted with diethyl acetamidomalonate 45, hydrolytically cleaved and the a-amino acid obtained was converted into the Boc-protected form under standard conditions. Another display option is from E. Reimann and 29
  • Boc- (D, L) -Dpa-0H (1 mmol) was hydrogenated in 12 mL MeOH together with catalytic amounts of 5% RI1 / Al 2 O 3 at 5 bar. After filtration and removal of the solvent in vacuo, the product was obtained in quantitative yield.
  • Boc- (D, L) - (3, 4, 5- (MeO) 3 ) Phe-OH was prepared by alkylation of methyl benzophenone with trimethoxybenzyl chloride, subsequent introduction of Boc protective groups and ester saponification.
  • H- (D, L) - ß, ß-Me 2 Cha-OH was prepared according to U. Schöllkopf, R. Meyer, L. Ann. Chem. 1977. 1174-82.
  • amino acids mentioned were converted into the Boc-protected form in each case using di-tert-butyl dicarbonate in water / dioxane and then recrystallized from ethyl acetate / hexane mixtures or column chromatographically on silica gel (mobile phase: ethyl acetate / petroleum ether - Mixtures) cleaned.
  • N-Boc-N- (tert-butyloxycarbonylmethylene) - (D) -cyclohexylglycine-cyclohexylammonium salt was prepared in an analogous manner from cyclohexylglycine as a starting material.
  • N-Boc-N- (tert-butyloxycarbonylmethylene) - (D) -cylcoheptyl-glycine or N-Boc-N- (tert-butoxycarbonylmethylene) - (D) -cyclopentylglycine derivative were derived from the corresponding Cycloheptyl and cyclopentylglycine compounds prepared.
  • N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 mL) and HC1 in dioxane (4N, 30 mL) was added. The mixture was then heated under reflux for 12 h. The solvent was spun off and H-Pyr-OMe hydrochloride was obtained as the product. Yield: 3.84 g (100%).
  • N- (t-Bu0 2 C-CH 2 ) -N-Boc- (D) -Cha-OH 8 g, 20.75 mmol was dissolved in dichloromethane (75 mL) and at -10 ° C with Ethyldiisopropylamine (15.5 mL, 89.24 mmol) was added. After stirring for 5 min at this temperature, a solution of H-Pyr-OMe hydrochloride (3.4 g, 20.75 mmol) in dichloromethane (25 mL) was added dropwise.
  • N-ethyldiisopropylamine (90 mL, 518.88 mmol) was added dropwise and the mixture was stirred for 5 min.
  • H-Pro-OBn x HC1 (12.54 g, 51.88 mmol) was then added and, after stirring for 5 min, 50% propanephosphonic anhydride solution in ethyl acetate (45.1 mL, 62.26 mmol) was diluted with Methylene chloride (45 mL) was added dropwise over 30 min. After stirring for 1 h at 0-5 ° C, the mixture was slowly warmed to RT and stirred for 12 h at RT. The mixture was diluted with methylene chloride and successively with sat.
  • the compounds (L) -proline and (L) -azetide carboxylic acid used as D building blocks can be purchased either as free amino acids or as Boc-protected compounds or as corresponding methyl esters. If the (L) -3, 4-dehydroproline or a correspondingly protected derivative was used as the D building block, the compounds shown were generally hydrogenated on the final stage to give the corresponding proline derivatives.
  • Reaction solution was diluted with dichloromethane, washed twice with water, three times with aqueous hydrochloric acid solution (PH ⁇ 2), once with water, dried over magnesium sulfate and concentrated in vacuo.
  • the crude product (8.0 g) was used in the subsequent reaction without further purification.
  • Boc-3, 4-dehydroproline (5 g, 23.4 mmol) and 5-aminomethyl-2-cyanothiophene hydrochloride (4.5 g, 25.8 mmol) were dissolved in dichloromethane (25 mL) and at 0 ° C with ethyldiisopropylamine (28 mL, 163.8 mmol) with a 50% solution of propanephosphonic anhydride in ethyl acetate (24.8 mL, 117 mmol). After stirring at 0 ° C. for 1 h, the mixture was warmed to RT and stirred at RT for 12 h.
  • the reaction mixture was diluted with dichloromethane, washed with sodium hydrogen sulfate solution (4x), sodium hydrogen carbonate solution (3x) and saturated sodium chloride solution (lx). After drying over sodium sulfate and filtering off the drying agent, the solvent was distilled off in a water jet vacuum. To split off the Boc group, the residue was added to dichloromethane (95 mL), stirred at RT, evaporated to dryness, codistilled twice with dichloromethane, concentrated again and purified by column chromatography. 6.6 g of the 41 wanted a product that was still slightly solvent-based.
  • the product obtained according to b) was dissolved in pyridine (68 ml) and triethylamine (11.5 ml). The reaction mixture was cooled to 0 ° C and saturated with hydrogen sulfide (the solution turned green). The reaction solution stood at RT overnight. The excess hydrogen sulfide was with
  • the product obtained according to e) was dissolved in 180 ml dichloromethane and dropwise mixed with ethereal hydrochloric acid solution (46.5 ml, approx. 5 mol / 1). After stirring overnight at RT, the solvent was distilled off in a water jet vacuum, dichloromethane was added to the residue and the solvent was distilled off in a water jet vacuum (2x).
  • the crude product (8.96 g) was dissolved in methanol and converted into the acetate salt via an ion exchanger (Fluka, order no. 00402).
  • Boc-prolin can be used instead of Boc- (L) -3, 4-dehydroproline, in which case the hydrogenation on the final stage is omitted.
  • Example 7 N- (Hydroxycarbonylmethylene) - (D) -adamantylalanyl-prolyl- [5- (2-amidino) -thienylmethyl] amide hydroacetate or N- (hydroxycarbonylmethylene) - (L) -adamantylalanyl-prolyl - [5- (2-amidino) thienylmethyl] amide hydroacetate.
  • the two diastereomeric compounds are separated on the final stage by means of reversed phase HPLC (acetonitrile / water and HOAc buffer).
  • the product obtained according to b) was dissolved in pyridine (16 ml) and triethylamine (8 ml). The reaction mixture was saturated with hydrogen sulfide at RT and stirred at RT overnight. The excess hydrogen sulfide was displaced with nitrogen and the reaction mixture was poured onto 200 ml of ice-cooled 5% sodium hydrogen sulfate solution. The mixture was extracted three times with 50 ml of ethyl acetate and the combined ethyl acetate phases were washed again with 5% sodium hydrogen sulfate solution in order to remove residues of pyridine. It was then washed again with saturated sodium bicarbonate solution, dried over sodium sulfate and the solvent was distilled off in a water jet vacuum. The crude product obtained (2.55 g) was used in the next step without further purification.
  • the crude product obtained according to d) (2.57 g, 3.43 mmol) was dissolved in 25 mL acetonitrile, mixed with 0.53 g (6.87 mmol) ammonium acetate and stirred for eight hours at 40 ° C. and overnight at RT. The solvent was then distilled off in a water jet vacuum, the residue was taken up in dichloromethane, the salts were filtered off with suction and the filtrate was concentrated. The crude product was purified by reversed phase HPLC (acetonitrile / water and acetic acid buffer) to give 67 mg of a yellow solid foam.
  • N- (tert.butoxycarbonylmethylene) - (N-Boc) - (D) -cyclohexylalanine was used instead of N- (tert.butoxycarbonylmethylene) - (N-Boc) - (D) - cyclohexylglycm.
  • Example 11 1- [N- (Hydroxycarbonylmethylene) - (D) -cyclohexyl-glycyl] -azetidine-2-cabonic acid- [5- (2-amidino) thienylmethyl] amide
  • N- (hydroxycarbonylethylene) - (D) - cyclohexylalanyl-prolyl- [5- (2-amidino) furylmethyl] amide hydroacetate can be prepared.
  • N- (Hydroxycarbonylmethylene) - (D) -cyclohexylalanyl-prolyl- [2- (5-amidino) -thiazolylmethyl] amide can be prepared according to the following reaction sequence: Coupling of (t-Bu0C-CH 2 -) - (Boc) - (D) -Cha-Pro-OH with H 2 N-CH 2 - (5-CN) -2-thiaz to (t-Bu0 2 C-CH 2 -) - (Boc) - (D) -Cha- Pro-NH-CH- (5-CN) -2-thiaz, amidine formation and subsequent deprotection analogous to Example 8c-f.
  • N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-prolyl- [2- (5-amidino) -thiazolylmethyl] amide can be prepared according to the following reaction sequence: Coupling of (t-Bu0 2 C-CH-) - (Boc ) - (D) -Chg-Pro-OH with H 2 N-CH 2 - (5-CN) -2-thiaz to (t-Bu0 2 C-CH 2 -) - (Boc) - (D) -Chg -Pro-NH-CH 2 - (5-CN) -2-thiaz, amidine formation and subsequent deprotection analogous to Example 8c-f. 49
  • N- (Hydroxycarbonylmethylene) - (D) -p-metoxyphenylalanyl-prolyl- [2- (5-amidino) -thienylmethyl] amide can be prepared analogously to WO98 / 06741 (Example 14) from the corresponding ABD and EF building blocks .
  • N- (Hydroxycarbonylmethylene) - (D) -p-trifluoromethylphenylalanyl-prolyl- [2- (5-amidino) -thienylmethyl] amide can be prepared analogously to WO98 / 06741 (Example 14) from the corresponding ABD and EF building blocks .
  • N- (methoxycarbonylmethylene) - (D) -cyclohexylalanyl-prolyl- [5- (2-hydroxyamidino) thienylmethyl] amide can be obtained by reacting (t-Bu0 2 C-CH 2 -) - (Boc) - ( D) -Cha-Pro-NH-CH- (2-CN) -5- thioph with hydroxylamm hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection and transesterification (HCl in methanol at room temperature).
  • hydroxylamm hydrochloride methanol, diisopropylethylamine, room temperature
  • Example 20 N- (Ethoxycarbonylmethylene) - (D) -cyclohexylalanyl-prolyl- [5- (2-hydroxyamidino) thienylmethyl] amide can be obtained by reacting (t-Bu0 2 C-CH 2 -) - (Boc ) - (D) -Cha-Pro-NH-CH 2 - (2-CN) -5- thioph with hydroxylamine hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection and transesterification (HCl in ethanol at room temperature).
  • hydroxylamine hydrochloride methanol, diisopropylethylamine, room temperature
  • N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-prolyl- [5- (2-hydroxyamidino) thienylmethyl] amide can be obtained by reacting (t-Bu0 2 C-CH 2 -) - (Boc) - ( D) -Chg-Pro-NH-CH 2 - (2-CN) -5- thioph with hydroxylamine hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection (HCl in dichloromethane at room temperature). 50
  • N- (methoxycarbonylmethylene) - (D) -cyclohexylglycyl-prolyl- [5- (2-hydroxyamidino) thienylmethyl] amide can be obtained by reacting (t-Bu0 2 C-CH 2 -) - (Boc) - ( D) -Chg-Pro-NH-CH 2 - (2-CN) -5- thioph with hydroxylamine hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection and transesterification (HCl in methanol at room temperature).
  • Example 23 N- (Ethoxycarbonylmethylene) - (D) -cyclohexylglycyl-prolyl- [5- (2-hydroxyamidino) thienylmethyl] amide can be obtained by reacting (t-Bu0 2 C-CH 2 -) - (Boc ) - (D) -Chg-Pro-NH-CH 2 - (2-CN) -5- thioph with hydroxylamine hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection and transesterification (HCl in ethanol at room temperature).
  • hydroxylamine hydrochloride methanol, diisopropylethylamine, room temperature
  • N- (Hydroxycarbonylmethylene) - (D) -cyclohexylglycyl-azetidine-2-carboxylic acid- [5- (2-hydroxyamidino) -thienylmethyl] amide can be obtained by reacting (t-Bu0 2 C-CH 2 -) - ( Boc) - (D) -Chg-Aze-NH-CH 2 - (2-CN) -5-thioph with hydroxylamine hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection (HCl in dichloromethane at room temperature).
  • Example 25 N- (Methoxycarbonylmethylene) - (D) -cyclohexylglycyl-azetidine-2-carboxylic acid- [5- (2-hydroxyamidino) -thienylmethyl] amide can be obtained by reacting (t-Bu0C-CH 2 -) - (Boc) - (D) -Chg-Aze-NH-CH 2 - (2-CN) -5-thioph with hydroxylamine hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection and transesterification (HCl in methanol at room temperature) .
  • hydroxylamine hydrochloride methanol, diisopropylethylamine, room temperature
  • N- (Ethoxycarbonylmethylene) - (D) -cyclohexylglycyl-azetidine-2-carboxylic acid - [5- (2-hydroxyamidino) thienylmethyl] amide can be obtained by reacting (t-Bu0 2 C-CH 2 -) - ( Boc) - (D) -Chg-Aze-NH-CH 2 - (2-CN) -5-thioph with hydroxylamine hydrochloride (methanol, diisopropylethylamine, room temperature) and subsequent deprotection and transesterification (HCl in ethanol at room temperature). 51
  • Chromozym GK (No. 709875, Boehringer, Mannheim, Germany)
  • the chromogenic test for determining kallikrein activity is carried out in microplates. 2 ⁇ l of the substance solution in DMSO are added to 93 ⁇ l buffer, mixed with a final concentration of 0.01 units / ml kallikrein. It is incubated at 20 to 25 ° C for 10 minutes. The test is started by adding 100 ⁇ l substrate (500 ⁇ mol / 1 final
  • Thrombin Reagent (Cat. No. 126 594, Boehringer, Mannheim, Germany)
  • test substance solution 50 ⁇ l test substance solution and 50 ⁇ l citrate plasma are incubated for 2 minutes at 37 ° C. (CL8, ball type, Bender & Hobein, Kunststoff, FRG). Then 100 ⁇ l thrombin reagent (37 ° C.) is added. The time until the fibrin clump is formed is determined. 52
  • Buffer Tris 50 mmol / 1, NaCl 154 mmol / 1, pH 8.0
  • the chromogenic test can be carried out in microtiter plates. 10 ⁇ l of substance solution in DMSO are added to 250 ⁇ l of buffer with thrombin (final concentration 0.1 NIH units / ml) and incubated for 5 minutes at 20 to 28 ° C. The test is carried out by adding 50 ⁇ l
  • Substrate solution in buffer (final concentration 100 ⁇ mol / 1) started, incubated at 28 ° C and stopped after 5 minutes by adding 50 ⁇ l citric acid (35%). The absorption is measured at 405/630 nm.
  • Venous blood from the cephalic vein of healthy drug-free test subjects is collected. The
  • Blood is mixed 9 to 1 with 0.13 molar trisodium citrate.
  • Platelet-rich plasma PRP
  • PPP Platelet-poor plasma
  • PRP and PPP can be stored for 3 hours at room temperature in closed PE containers.
  • the platelet concentration is measured with a cell counter and should be between 2.5 to
  • the platelet aggregation is measured turbitrimetrically at 37 ° C. (PAP 4, Biodata Corporation, Horsham,
  • thrombin Before thrombin is added, 215.6 ul PRP for 3 minutes with 2.2 ul test substance 53 incubated and then stirred at 1000 rpm for 2 minutes. At a final concentration of 0.15 NIH-Units / ml, 2.2 ⁇ l thrombin solution lead to the maximum agregation effect at 37 ° C / 1000 rpm.
  • the inhibited effect of the test substances is determined by the aggregation rate (slope) of thrombin without substance with the Rate of thrombin is compared with test substance at different concentrations.

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Abstract

L'invention concerne des composés de formule A-B-D-E-F, dans laquelle A, B, D, E et F ont la signification mentionnée dans la description, ainsi que leur procédé de fabrication. Ces nouveaux composés sont utiles pour la préparation de médicaments.
EP99903676A 1998-01-26 1999-01-23 Amidines heterocycliques utilisees comme inhibiteurs de la kallicreine Withdrawn EP1049673A1 (fr)

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EP1054886B1 (fr) * 1998-02-09 2002-09-04 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines et guanidines utiles en tant qu'inhibiteurs de protease et plus particulierement en tant qu'inhibiteurs d'urokinase
KR20000047461A (ko) * 1998-12-29 2000-07-25 성재갑 트롬빈 억제제
CZ20012858A3 (cs) * 1999-02-09 2002-05-15 3-Dimensional Pharmaceuticals, Inc. Heteroarylamidiny, methylamidininy a guanidiny jako inhibitory proteasy
CA2370267A1 (fr) * 1999-04-09 2000-10-19 Basf Aktiengesellschaft Promedicaments d'inhibiteurs de la thrombine
IL145771A0 (en) * 1999-04-09 2002-07-25 Basf Ag Low-molecular inhibitors of complement proteases
AR023510A1 (es) 1999-04-21 2002-09-04 Astrazeneca Ab Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina.
EP1487826A4 (fr) * 2002-03-22 2005-06-29 Lg Life Sciences Ltd NOUVELLES FORMES CRISTALLINES DE (2S)-N-5-(AMINO(IMINO)METHYL)-2-THIENYLMETHYL-1-(2R)-2-((CARBOXYMETHYL)AMINO)-3,3-DIPHENYLPROPANOYL-2-PYRROLIDINECARBOXAMIDE . nH2O
PL372596A1 (en) * 2002-03-22 2005-07-25 Lg Life Sciences Ltd. Maleic acid salt of (2s)-n-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2r)-2-[(carboxymethyl)amino]3,3-diphenylpropanoyl}-2-pyrrolidine carboxamide and a process for
WO2004002985A1 (fr) * 2002-06-27 2004-01-08 Lg Life Sciences Ltd. Compose peptidique inhibiteur de la thrombine
EP1736465A4 (fr) 2004-03-31 2009-06-17 Ajinomoto Kk Dérivés d'aniline
DE102005035250A1 (de) 2005-07-25 2007-02-01 Archimica Gmbh Verfahren zur Herstellung von Nitrilen durch Eliminierungsreaktionen

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SE9301916D0 (sv) * 1993-06-03 1993-06-03 Ab Astra New peptides derivatives
ZA951617B (en) * 1994-03-04 1997-02-27 Lilly Co Eli Antithrombotic agents.
DE19504504A1 (de) * 1995-02-10 1996-08-14 Basf Ag Heterocyclische Thrombininhibitoren
DE19506610A1 (de) * 1995-02-24 1996-08-29 Basf Ag Thrombininhibitoren
PL321759A1 (en) * 1995-02-17 1997-12-22 Basf Ag Novel thrombosin inhibitors
DE19632773A1 (de) * 1996-08-14 1998-02-19 Basf Ag Neue Thrombininhibitoren

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